title: Synthesis, docking, and biological studies of phenanthrene β-diketo acids as novel HIV-1 integrase inhibitors.
abstract: In the present study we report the synthesis of halogen-substituted phenanthrene β-diketo acids as new HIV-1 integrase inhibitors. The target phenanthrenes were obtained using both standard thermal- and microwave-assisted synthesis. 4-(6-Chlorophenanthren-2-yl)-2,4-dioxobutanoic acid (18) was the most active compound of the series, inhibiting both 3'-end processing (3'-P) and strand transfer (ST) with IC50 values of 5 and 1.3 μM, respectively. Docking studies revealed two predominant binding modes that were distinct from the binding modes of raltegravir and elvitegravir, and suggest a novel binding region in the IN active site. Moreover, these compounds are predicted not to interact significantly with some of the key amino acids (Q148 and N155) implicated in viral resistance. Therefore, this series of compounds can further be investigated for a possible chemotype to circumvent resistance to clinical HIV-1 IN inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 847 Monroe Avenue, Suite 327, Memphis 38163, USA.
authors.forename: Horrick
authors.initials: H
authors.lastname: Sharma
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Cheng
authors.forename: John K
authors.initials: JK
authors.lastname: Buolamwini
mesh_terms: D015195:Drug Design; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D010616:Phenanthrenes
keywords: Docking; HIV-1; HIV-1 integrase; Phenanthrene β-diketo acids; ST inhibitors